Sequestering subunit and related compositions and methods

ABSTRACT

A sequestering subunit comprising an aversive agent and a blocking agent, wherein the blocking agent substantially prevents release of the aversive agent from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours; a composition comprising a sequestering subunit in releasable form, wherein, optionally, the mechanical fragility of the sequestering subunit is the same as the mechanical fragility of the therapeutic agent in releasable form; a capsule or tablet comprising a sequestering subunit and a therapeutic agent; and a method of preventing abuse of a therapeutic agent.

FIELD OF THE INVENTION

This invention pertains to a sequestering subunit comprising an aversiveagent and a blocking agent, and related compositions and methods of use,such as in the prevention of abuse of a therapeutic agent.

BACKGROUND OF THE INVENTION

Opioids, also called opioid agonists, are a class of drugs that exhibitopium-like or morphine-like properties. The opioids are employedprimarily as moderate to strong analgesics, but have many otherpharmacological effects as well, including drowsiness, respiratorydepression, changes in mood, and mental clouding without a resultingloss of consciousness. Because of these other pharmacological effects,opioids have become the subject of dependence and abuse. Therefore, amajor concern associated with the use of opioids is the diversion ofthese drugs from the illicit user, e.g., an addict.

Physical dependence may develop upon repeated administrations orextended use of opioids. Physical dependence is gradually manifestedafter stopping opioid use or is precipitously manifested (e.g., within afew minutes) after administration of a narcotic antagonist (referred to“precipitated withdrawal”). Depending upon the drug upon whichdependence has been established and the duration of use and dose,symptoms of withdrawal vary in number and kind, duration and severity.The most common symptoms of the withdrawal syndrome include anorexia,weight loss, pupillary dilation, chills alternating with excessivesweating, abdominal cramps, nausea, vomiting, muscle spasms,hyperirritability, lacrimation, rinorrhea, goose flesh and increasedheart rate. Natural abstinence syndromes typically begin to occur 24-48hours after the last dose, reach maximum intensity about the third dayand may not begin to decrease until the third week. Precipitatedabstinence syndromes produced by administration of an opioid antagonistvary in intensity and duration with the dose and the specificantagonist, but generally vary from a few minutes to several hours inlength.

Psychological dependence or addiction to opioids is characterized bydrug-seeking behavior directed toward achieving euphoria and escapefrom, e.g., psychosocioeconomic pressures. An addict will continue toadminister opioids for non-medicinal purposes and in the face ofself-harm.

Although opioids, such as morphine, hydromorphone, hydrocodone andoxycodone, are effective in the management of pain, there has been anincrease in their abuse by individuals who are psychologically dependenton opioids or who misuse opioids for non-therapeutic reasons. Previousexperience with other opioids has demonstrated a decreased abusepotential when opioids are administered in combination with a narcoticantagonist, especially in patients who are ex-addicts (Weinhold et al.,Drug and Alcohol Dependence 30:263-274 (1992); and Mendelson et al.,Clin. Pharm. Ther. 60:105-114 (1996)). These combinations, however, donot contain the opioid antagonist that is in a sequestered form. Rather,the opioid antagonist is released in the gastrointestinal system whenorally administered and is made available for absorption, relying on thephysiology of the host to metabolize differentially the agonist andantagonist and negate the agonist effects.

Previous attempts to control the abuse potential associated with opioidanalgesics include, for example, the combination of pentazocine andnaloxone in tablets, commercially available in the United States asTalwin®Nx from Sanofi-Winthrop, Canterbury, Australia. Talwin®Nxcontains pentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. Talwin®Nx is indicated for therelief of moderate to severe pain. The amount of naloxone present inthis combination has low activity when taken orally, and minimallyinterferes with the pharmacologic action of pentazocine. However, thisamount of naloxone given parenterally has profound antagonistic actionto narcotic analgesics. Thus, the inclusion of naloxone is intended tocurb a form of misuse of oral pentazocine, which occurs when the dosageform is solubilized and injected. Therefore, this dosage has lowerpotential for parenteral misuse than previous oral pentazocineformulations. However, it is still subject to patient misuse and abuseby the oral route, for example, by the patient taking multiple doses atonce. A fixed combination therapy comprising tilidine (50 mg) andnaloxone (4 mg) has been available in Germany for the management ofsevere pain since 1978 (Valoron®, Goedecke). The rationale for thecombination of these drugs is effective pain relief and the preventionof tilidine addiction through naloxone-induced antagonisms at thetilidine receptors. A fixed combination of buprenorphine and naloxonewas introduced in 1991 in New Zealand (Terngesic®Nx, Reckitt & Colman)for the treatment of pain.

International Patent Application No. PCT/US01/04346 (WO 01/58451) toEuroceltique, S. A., describes the use of a pharmaceutical compositionthat contains a substantially non-releasing opioid antagonist and areleasing opioid agonist as separate subunits that are combined into apharmaceutical dosage form, e.g., tablet or capsule. However, becausethe agonist and antagonist are in separate subunits, they can be readilyseparated. Further, providing the agonist and antagonist as separatesubunits, tablets are more difficult to form due to the mechanicalsensitivity of some subunits comprising a sequestering agent.

The benefits of the abuse-resistant dosage form are especially great inconnection with oral dosage forms of strong opioid agonists (e.g.,morphine, hydromorphone, oxycodone or hydrocodone), which providevaluable analgesics but are prone to being abused. This is particularlytrue for sustained-release opioid agonist products, which have a largedose of a desirable opioid agonist intended to be released over a periodof time in each dosage unit. Drug abusers take such sustained releaseproduct and crush, grind, extract or otherwise damage the product sothat the full contents of the dosage form become available for immediateabsorption.

Such abuse-resistant, sustained-release dosage forms have been describedin the art (see, for example, U.S. Application Nos. 2003/0124185 and2003/0044458). However, it is believed that substantial amounts of theopioid antagonist or other aversive agent found in these sequesteredforms are released over time (usually less than 24 hours) due to theosmotic pressure that builds up in the core of the sequestered form, aswater permeates through the sequestered form into the core. The highosmotic pressure inside the core of the sequestered form causes theopioid antagonist or aversive agent to be pushed out of the sequesteredform, thereby causing the opioid antagonist or aversive agent to bereleased from the sequestered form.

In view of the foregoing drawbacks of the sequestered forms of the priorart, there exists a need in the art for a sequestered form of an opioidantagonist or other aversive agent that is not substantially releasedfrom the sequestered form due to osmotic pressure.

The invention provides such a sequestering form of an opioid antagonistor aversive agent. This and other objects and advantages of theinvention, as well as additional inventive features, will be apparentfrom the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

The invention provides a sequestering subunit comprising an aversiveagent and a blocking agent, wherein the blocking agent substantiallyprevents release of the aversive agent from the sequestering subunit inthe gastrointestinal tract for a time period that is greater than 24hours.

Also provided by the invention is a composition comprising asequestering subunit of the invention and a therapeutic agent inreleasable form. Optionally, the mechanical fragility of thesequestering subunit is the same as the mechanical fragility of thetherapeutic agent in releasable form.

The invention also provides a capsule suitable for oral administrationcomprising a plurality of composite subunits, wherein each compositesubunit comprises the sequestering subunit coated with a therapeuticagent in releasable form. A capsule suitable for oral administrationcomprising a plurality of sequestering subunits of the invention and aplurality of therapeutic subunits, each of which comprises a therapeuticagent in releasable form is further provided.

Further provided is a tablet suitable for oral administration comprisinga first layer comprising a sequestering subunit of the invention and asecond layer comprising a therapeutic agent in releasable form, whereinthe first layer is coated with the second layer. The invention alsoprovides a tablet suitable for oral administration comprising a singlelayer comprising a therapeutic agent in releasable form and a pluralityof the sequestering subunits of the invention dispersed throughout thelayer.

The invention further provides a method of preventing abuse of atherapeutic agent, which method comprises incorporating the therapeuticagent in any composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a sequestering subunit comprising an aversiveagent and a blocking agent, wherein the blocking agent substantiallyprevents release of the aversive agent from the sequestering subunit inthe gastrointestinal tract for a time period that is greater than 24hours.

With respect to the invention, the term “sequestering subunit” as usedherein refers to any means for containing an aversive agent andpreventing or substantially preventing the release thereof in thegastrointestinal tract when intact, i.e., when not tampered with. Theterm “blocking agent” as used herein refers to the means by which thesequestering subunit is able to prevent substantially the aversive agentfrom being released.

The terms “substantially prevents,” “prevents,” or any words stemmingtherefrom, as used herein, means that the aversive agent issubstantially not released from the sequestering subunit in thegastrointestinal tract. By “substantially not released” is meant thatthe aversive agent may be released in a small amount, but the amountreleased does not affect or does not significantly affect the analgesicefficacy when the dosage form is orally administered to a host, e.g., amammal (e.g., a human), as intended. The terms “substantially prevents,”“prevents,” or any words stemming therefrom, as used herein, does notnecessarily imply a complete or 100% prevention. Rather, there arevarying degrees of prevention of which one of ordinary skill in the artrecognizes as having a potential benefit. In this regard, the blockingagent substantially prevents or prevents the release of the aversiveagent to the extent that at least about 80% of the aversive agent isprevented from being released from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.Preferably, the blocking agent prevents release of at least about 90% ofthe aversive agent from the sequestering subunit in the gastrointestinaltract for a time period that is greater than 24 hours. More preferably,the blocking agent prevents release of at least about 95% of theaversive agent from the sequestering subunit. Most preferably, theblocking agent prevents release of at least about 99% of the aversiveagent from the sequestering subunit in the gastrointestinal tract for atime period that is greater than 24 hours.

The blocking agent prevents or substantially prevents the release of theaversive agent in the gastrointestinal tract for a time period that isgreater than 24 hours, e.g., between 24 and 25 hours, 30 hours, 35hours, 40 hours, 45 hours, 48 hours, 50 hours, 55 hours, 60 hours, 65hours, 70 hours, 72 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95hours, or 100 hours; etc. Preferably, the time period for which therelease of the aversive agent is prevented or substantially prevented inthe gastrointestinal tract is at least about 48 hours. More preferably,the blocking agent prevents or substantially prevents the release for atime period of at least about 72 hours.

For purposes of this invention, the amount of the aversive agentreleased after oral administration can be measured in-vitro bydissolution testing as described in the United States Pharmacopeia(USP26) in chapter <711>Dissolution. For example, using 900 mL of 0.1 NHCl, Apparatus 2 (Paddle), 75 rpm; at 37° C. to measure release atvarious times from the dosage unit. Other methods of measuring therelease of an aversive agent from a sequestering subunit over a givenperiod of time are known in the art. See, e.g., USP26 and Examples 1 and2 below.

Without being bound to any particular theory, it is believed that thesequestering subunit of the invention overcomes the limitations of thesequestered forms of an aversive agent known in the art in that thesequestering subunit of the invention reduces osmotically-driven releaseof the aversive agent from the sequestering subunit. Furthermore, it isbelieved that the present inventive sequestering subunit reduces therelease of the aversive agent for a longer period of time (e.g., greaterthan 24 hours) in comparison to the sequestered forms of aversive agentsknown in the art. The fact that the sequestered subunit of the inventionprovides a longer prevention of release of the aversive agent isparticularly relevant, since precipitated withdrawal could occur afterthe time for which the therapeutic agent is released and acts. It iswell known that the gastrointestinal tract transit time for individualsvaries greatly within the population. Hence, the residue of the dosageform may be retained in the tract for longer than 24 hours, and in somecases for longer than 48 hours. It is further well known that opioidanalgesics cause decreased bowel motility, further prolonginggastrointestinal tract transit time. Currently, sustained-release formshaving an effect over a 24 hour time period have been approved by theFood and Drug Administration. In this regard, the present inventivesequestering subunit provides prevention of release of the aversiveagent for a time period that is greater than 24 hours when thesequestering subunit has not been tampered.

The sequestering subunit of the invention is designed to preventsubstantially the release of the aversive agent when intact. By “intact”is meant that a dosage form has not undergone tampering. The term“tampering” is meant to include any manipulation by mechanical, thermaland/or chemical means, which changes the physical properties of thedosage form. The tampering can be, for example, crushing, shearing,grinding, chewing, dissolution in a solvent, heating (for example,greater than about 45° C.), or any combination thereof. When thesequestering subunit of the invention has been tampered with, theaversive agent is immediately released from the sequestering subunit.

By “subunit” is meant to include a composition, mixture, particle; etc.,that can provide a dosage form (e.g., an oral dosage form) when combinedwith another subunit. The subunit can be in the form of a bead, pellet,granule, spheroid, or the like, and can be combined with additional sameor different subunits, in the form of a capsule, tablet or the like, toprovide a dosage form, e.g., an oral dosage form.

The blocking agent of the present inventive sequestering subunit can bea system comprising a first aversive agent-impermeable material and acore. By “aversive agent-impermeable material” is meant any materialthat is substantially impermeable to the aversive agent, such that theaversive agent is substantially not released from the sequesteringsubunit. The term “substantially impermeable” as used herein does notnecessarily imply complete or 100% impermeability. Rather, there arevarying degrees of impermeability of which one of ordinary skill in theart recognizes as having a potential benefit. In this regard, theaversive agent-impermeable material substantially prevents or preventsthe release of the aversive agent to an extent that at least about 80%of the aversive agent is prevented from being released from thesequestering subunit in the gastrointestinal tract for a time periodthat is greater than 24 hours. Preferably, the aversiveagent-impermeable material prevents release of at least about 90% of theaversive agent from the sequestering subunit in the gastrointestinaltract for a time period that is greater than 24 hours. More preferably,the aversive agent-impermeable material prevents release of at leastabout 95% of the aversive agent from the sequestering subunit. Mostpreferably, the aversive agent-impermeable material prevents release ofat least about 99% of the aversive agent from the sequestering subunitin the gastrointestinal tract for a time period that is greater than 24hours. The aversive agent-impermeable material prevents or substantiallyprevents the release of the aversive agent in the gastrointestinal tractfor a time period that is greater than 24 hours, and desirably, at leastabout 48 hours. More desirably, the aversive agent-impermeable materialprevents or substantially prevents the release of the adversive agentfrom the sequestering subunit for a time period of at least about 72hours.

Preferably, the first aversive agent-impermeable material comprises ahydrophobic material, such that the antagonist is not released orsubstantially not released during its transit through thegastrointestinal tract when administered orally as intended, withouthaving been tampered with. Suitable hydrophobic materials for use in theinvention are described herein and set forth below. The hydrophobicmaterial is preferably a pharmaceutically acceptable hydrophobicmaterial. Preferably, the pharmaceutically acceptable hydrophobicmaterial comprises a cellulose polymer.

It is preferred that the first aversive agent-impermeable materialcomprises a polymer insoluble in the gastrointestinal tract. One ofordinary skill in the art appreciates that a polymer that is insolublein the gastrointestinal tract will prevent the release of the aversiveagent upon ingestion of the sequestering subunit. The polymer can be acellulose or an acrylic polymer. Desirably, the cellulose is selectedfrom the group consisting of ethylcellulose, cellulose acetate,cellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, andcombinations thereof. Ethylcellulose includes, for example, one that hasan ethoxy content of about 44 to about 55%. Ethylcellulose can be usedin the form of an aqueous dispersion, an alcoholic solution, or asolution in other suitable solvents. The cellulose can have a degree ofsubstitution (D.S.) on the anhydroglucose unit, from greater than zeroand up to 3 inclusive. By “degree of substitution” is meant the averagenumber of hydroxyl groups on the anhydroglucose unit of the cellulosepolymer that are replaced by a substituting group. Representativematerials include a polymer selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate, monocellulosealkanylate, dicellulose alkanylate, tricellulose alkanylate,monocellulose alkenylates, dicellulose alkenylates, tricellulosealkenylates, monocellulose aroylates, dicellulose aroylates, andtricellulose aroylates.

More specific celluloses include cellulose propionate having a D.S. of1.8 and a propyl content of 39.2 to 45 and a hydroxy content of 2.8 to5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%, a butyryl content of 17to 53% and a hydroxy content of 0.5 to 4.7%; cellulose triacylate havinga D.S. of 2.9 to 3, such as cellulose triacetate, cellulose trivalerate,cellulose trilaurate, cellulose tripatmitate, cellulose trisuccinate,and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to2.6, such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate, and coesters of cellulose, such ascellulose acetate butyrate, cellulose acetate octanoate butyrate, andcellulose acetate propionate.

Additional cellulose polymers useful for preparing a sequesteringsubunit of the invention includes acetaldehyde dimethyl celluloseacetate, cellulose acetate ethylcarbamate, cellulose acetatemethycarbamate, and cellulose acetate dimethylaminocellulose acetate.

The acrylic polymer preferably is selected from the group consisting ofmethacrylic polymers, acrylic acid and methacrylic acid copolymers,methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), glycidylmethacrylate copolymers, and combinations thereof. An acrylic polymeruseful for preparation of a sequestering subunit of the inventionincludes acrylic resins comprising copolymers synthesized from acrylicand methacrylic acid esters (e.g., the copolymer of acrylic acid loweralkyl ester and methacrylic acid lower alkyl ester) containing about0.02 to about 0.03 mole of a tri (lower alkyl) ammonium group per moleof the acrylic and methacrylic monomer used. An example of a suitableacrylic resin is ammonio methacrylate copolymer NF21, a polymermanufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under theEudragit® trademark. Eudragit RS30D is preferred. Eudragit® is awater-insoluble copolymer of ethyl acrylate (EA), methyl methacrylate(MM) and trimethylammoniumethyl methacrylate chloride (TAM) in which themolar ratio of TAM to the remaining components (EA and MM) is 1:40.Acrylic resins, such as Eudragit®, can be used in the form of an aqueousdispersion or as a solution in suitable solvents.

In another preferred embodiment, the aversive agent-impermeable materialis selected from the group consisting of polylactic acid, polyglycolicacid, a co-polymer of polylactic acid and polyglycolic acid, andcombinations thereof. In certain other embodiments, the hydrophobicmaterial includes a biodegradable polymer comprising apoly(lactic/glycolic acid) (“PLGA”), a polylactide, a polyglycolide, apolyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes,polysaccharides, proteinaceous polymers, polyesters, polydioxanone,polygluconate, polylactic-acid-polyethylene oxide copolymers,poly(hydroxybutyrate), polyphosphoester or combinations thereof.

Preferably, the biodegradable polymer comprises a poly(lactic/glycolicacid), a copolymer of lactic and glycolic acid, having a molecularweight of about 2,000 to about 500,000 daltons. The ratio of lactic acidto glycolic acid is preferably from about 100:1 to about 25:75, with theratio of lactic acid to glycolic acid of about 65:35 being morepreferred.

Poly(lactic/glycolic acid) can be prepared by the procedures set forthin U.S. Pat. No. 4,293,539 (Ludwig et al.), which is incorporated hereinby reference. In brief, Ludwig prepares the copolymer by condensation oflactic acid and glycolic acid in the presence of a readily removablepolymerization catalyst (e.g., a strong ion-exchange resin such as DowexHCR-W2-H). The amount of catalyst is not critical to the polymerization,but typically is from about 0.01 to about 20 parts by weight relative tothe total weight of combined lactic acid and glycolic acid. Thepolymerization reaction can be conducted without solvents at atemperature from about 100° C. to about 250° C. for about 48 to about 96hours, preferably under a reduced pressure to facilitate removal ofwater and by-products. Poly(lactic/glycolic acid) is then recovered byfiltering the molten reaction mixture in an organic solvent, such asdichloromethane or acetone, and then filtering to remove the catalyst.

Suitable plasticizers, for example, acetyl triethyl citrate, acetyltributyl citrate, triethyl citrate, diethyl phthalate, dibutylphthalate, or dibutyl sebacate, also can be admixed with the polymerused to make the sequestering subunit. Additives, such as coloringagents, talc and/or magnesium stearate, and other additives also can beused in making the present inventive sequestering subunit.

When the blocking agent is a system comprising a first aversiveagent-impermeable material and a core, the sequestering subunit can bein one of several different forms. For example, the system can furthercomprise a second aversive agent-impermeable material, in which case thesequestering unit comprises an aversive agent, a first aversiveagent-impermeable material, a second aversive agent-impermeablematerial, and a core. In this instance, the core is coated with thefirst aversive agent-impermeable material, which, in turn, is coatedwith the aversive agent, which, in turn, is coated with the secondaversive agent-impermeable material. The first aversiveagent-impermeable material and second aversive agent-impermeablematerial substantially prevent release of the aversive agent from thesequestering subunit in the gastrointestinal tract for a time periodthat is greater than 24 hours. In some instances, it is preferable thatthe first aversive agent-impermeable material is the same as the secondaversive agent-impermeable material. In other instances, the firstaversive agent-impermeable material is different from the secondaversive agent-impermeable material. It is within the skill of theordinary artisan to determine whether or not the first and secondaversive agent-impermeable materials should be the same or different.Factors that influence the decision as to whether the first and secondaversive agent-impermeable materials should be the same or different caninclude whether a layer to be placed over the aversive agent-impermeablematerial requires certain properties to prevent dissolving part or allof the aversive agent-impermeable layer when applying the next layer orproperties to promote adhesion of a layer to be applied over theaversive agent-impermeable layer.

Alternatively, the aversive agent can be incorporated into the core, andthe core is coated with the first aversive agent-impermeable material.In this case, the invention provides a sequestering subunit comprisingan aversive agent, a core and a first aversive agent-impermeablematerial, wherein the aversive agent is incorporated into the core andthe core is coated with the first aversive agent-impermeable material,and wherein the first aversive agent-impermeable material substantiallyprevents release of the aversive agent from the sequestering subunit inthe gastrointestinal tract for a time period that is greater than 24hours. By “incorporate” and words stemming therefrom, as used herein ismeant to include any means of incorporation, e.g., homogeneousdispersion of the aversive agent throughout the core, a single layer ofthe aversive agent coated on top of a core, or a multi-layer system ofthe aversive agent, which comprises the core.

In another alternative embodiment, the core comprises a water-insolublematerial, and the core is coated with the aversive agent, which, inturn, is coated with the first aversive agent-impermeable material. Inthis case, the invention further provides a sequestering subunitcomprising an aversive agent, a first aversive agent-impermeablematerial, and a core, which comprises a water-insoluble material,wherein the core is coated with the aversive agent, which, in turn, iscoated with the first aversive agent-impermeable material, and whereinthe first aversive agent-impermeable material substantially preventsrelease of the aversive agent from the sequestering subunit in thegastrointestinal tract for a time period that is greater than 24 hours.The term “water-insoluble material” as used herein means any materialthat is substantially water-insoluble. The term “substantiallywater-insoluble” does not necessarily refer to complete or 100%water-insolubility. Rather, there are varying degrees of waterinsolubility of which one of ordinary skill in the art recognizes ashaving a potential benefit. Preferred water-insoluble materials include,for example, microcrystalline cellulose, a calcium salt, and a wax.Calcium salts include, but are not limited to, a calcium phosphate(e.g., hydroxyapatite, apatite; etc.), calcium carbonate, calciumsulfate, calcium stearate, and the like. Waxes include, for example,carnuba wax, beeswax, petroleum wax, candelilla wax, and the like.

For purposes of the invention, the aversive agent can be any agent thatnegates the effect of the therapeutic agent or produces an unpleasant orpunishing stimulus or effect, which will deter or cause avoidance oftampering with the sequestering subunit or compositions comprising thesame. Desirably, the aversive agent does not harm a host by itsadministration or consumption but has properties that deter itsadministration or consumption, e.g., by chewing and swallowing or bycrushing and snorting, for example. The aversive agent can have a strongor foul taste or smell, provide a burning or tingling sensation, cause alachrymation response, nausea, vomiting, or any other unpleasant orrepugnant sensation, or color tissue, for example. Preferably, theaversive agent is selected from the group consisting of an antagonist ofa therapeutic agent, a bittering agent, a dye, a gelling agent, and anirritant. Exemplary aversive agents include capsaicin, dye, bitteringagents and emetics.

By “antagonist of a therapeutic agent” is meant any drug or molecule,naturally-occurring or synthetic, that binds to the same target molecule(e.g., a receptor) of the therapeutic agent, yet does not produce atherapeutic, intracellular, or in vivo response. In this regard, theantagonist of a therapeutic agent binds to the receptor of thetherapeutic agent, thereby preventing the therapeutic agent from actingon the receptor, thereby preventing the achievement of a “high” in thehost.

The therapeutic agent can be any medicament. Preferably, the therapeuticagent is one that is addictive (physically and/or psychologically) andtypically leads to abuse. In this regard, the therapeutic agent can bean opioid agonist. By “opioid” is meant to include a drug, hormone, orother chemical or biological substance, natural or synthetic, having asedative, narcotic, or otherwise similar effect(s) to those containingopium or its natural or synthetic derivatives. By “opioid agonist,”sometimes used herein interchangeably with terms “opioid” and “opioidanalgesic,” is meant to include one or more opioid agonists, eitheralone or in combination, and is further meant to include the base of theopioid, mixed or combined agonist-antagonists, partial agonists,pharmaceutically acceptable salts thereof, stereoisomers thereof, ethersthereof, esters thereof, and combinations thereof.

The pharmaceutically acceptable salts of an opioid agonist include metalsalts, such as sodium salt, potassium salt, cesium salt, and the like;alkaline earth metals, such as calcium salt, magnesium salt, and thelike; organic amine salts, such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and the like;inorganic acid salts, such as hydrochloride, hydrobromide, sulfate,phosphate, and the like; organic acid salts, such as formate, acetate,trifluoroacetate, maleate, tartrate, and the like; sulfonates, such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts, such as arginate, asparginate, glutamate, and thelike.

Opioid agonists include, for example, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydroetorphine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl,heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenazocine,phenomorphan, phenoperidine, piminodine, piritramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tramadol,tilidine, derivatives or complexes thereof, pharmaceutically acceptablesalts thereof, and combinations thereof. Preferably, the opioid agonistis selected from the group consisting of hydrocodone, hydromorphone,oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine,buprenorphine, derivatives or complexes thereof, pharmaceuticallyacceptable salts thereof, and combinations thereof. Most preferably, theopioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. Ina preferred embodiment, the opioid agonist comprises oxycodone orhydrocodone and is present in the dosage form in an amount of about 15to about 45 mg, and the opioid antagonist comprises naltrexone and ispresent in the dosage form in an amount of about 0.5 to about 5 mg.

Equianalgesic doses of these opioids, in comparison to a 15 mg dose ofhydrocodone, are set forth in Table 1 below:

TABLE 1 Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0

Hydrocodone is a semisynthetic narcotic analgesic and antitussive withmultiple nervous system and gastrointestinal actions. Chemically,hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one, and is alsoknown as dihydrocodeinone. Like other opioids, hydrocodone can behabit-forming and can produce drug dependence of the morphine type. Likeother opium derivatives, excess doses of hydrocodone will depressrespiration.

Oral hydrocodone is also available in Europe (e.g., Belgium, Germany,Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussiveagent. A parenteral formulation is also available in Germany as anantitussive agent. For use as an analgesic, hydrocodone bitartrate iscommonly available in the United States only as a fixed combination withnon-opiate drugs (e.g., ibuprofen, acetaminophen, aspirin; etc.) forrelief of moderate to moderately severe pain.

A common dosage form of hydrocodone is in combination with acetaminophenand is commercially available, for example, as Lortab® in the UnitedStates from UCB Pharma, Inc. (Brussels, Belgium), as 2.5/500 mg, 5/500mg, 7.5/500 mg and 10/500 mg hydrocodone/acetaminophen tablets. Tabletsare also available in the ratio of 7.5 mg hydrocodone bitartrate and 650mg acetaminophen and a 7.5 mg hydrocodone bitartrate and 750 mgacetaminophen. Hydrocodone, in combination with aspirin, is given in anoral dosage form to adults generally in 1-2 tablets every 4-6 hours asneeded to alleviate pain. The tablet form is 5 mg hydrocodone bitartrateand 224 mg aspirin with 32 mg caffeine; or 5 mg hydrocodone bitartrateand 500 mg aspirin. Another formulation comprises hydrocodone bitartrateand ibuprofen. Vicoprofen®, commercially available in the U.S. fromKnoll Laboratories (Mount Olive, N.J.), is a tablet containing 7.5 mghydrocodone bitartrate and 200 mg ibuprofen. The invention iscontemplated to encompass all such formulations, with the inclusion ofthe opioid antagonist and/or aversive agent in sequestered form as partof a subunit comprising an opioid agonist.

Oxycodone, chemically known as4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one, is an opioidagonist whose principal therapeutic action is analgesia. Othertherapeutic effects of oxycodone include anxiolysis, euphoria andfeelings of relaxation. The precise mechanism of its analgesic action isnot known, but specific CNS opioid receptors for endogenous compoundswith opioid-like activity have been identified throughout the brain andspinal cord and play a role in the analgesic effects of this drug.

Oxycodone is commercially available in the United States, e.g., asOxycotin® from Purdue Pharma L.P. (Stamford, Conn.), ascontrolled-release tablets for oral administration containing 10 mg, 20mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxylR™, also fromPurdue Pharma L.P., as immediate-release capsules containing 5 mgoxycodone hydrochloride. The invention is contemplated to encompass allsuch formulations, with the inclusion of an opioid antagonist and/oraversive agent in sequestered form as part of a subunit comprising anopioid agonist.

Oral hydromorphone is commercially available in the United States, e.g.,as Dilaudid® from Abbott Laboratories (Chicago, Ill.).

Oral morphine is commercially available in the United States, e.g., asKadian® from Faulding Laboratories (Piscataway, N.J.).

In embodiments in which the opioid agonist comprises hydrocodone, thesustained-release oral dosage forms can include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. Insustained-release oral dosage forms where hydromorphone is thetherapeutically active opioid, it is included in an amount from about 2mg to about 64 mg hydromorphone hydrochloride. In another embodiment,the opioid agonist comprises morphine, and the sustained-release oraldosage forms of the invention include from about 2.5 mg to about 800 mgmorphine, by weight. In yet another embodiment, the opioid agonistcomprises oxycodone and the sustained-release oral dosage forms includefrom about 2.5 mg to about 800 mg oxycodone. In certain preferredembodiments, the sustained-release oral dosage forms include from about20 mg to about 30 mg oxycodone. Controlled release oxycodoneformulations are known in the art. The following documents describevarious controlled-release oxycodone formulations suitable for use inthe invention described herein, and processes for their manufacture:U.S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656,295, which areincorporated herein by reference. The opioid agonist can comprisetramadol and the sustained-release oral dosage forms can include fromabout 25 mg to 800 mg tramadol per dosage unit.

In the instance when the therapeutic agent is an opioid agonist, theaversive agent preferably is an opioid antagonist, such as naltrexone,naloxone, nalmefene, cyclazacine, levallorphan, derivatives or complexesthereof, pharmaceutically acceptable salts thereof, and combinationsthereof. More preferably, the opioid antagonist is naloxone ornaltrexone. By “opioid antagonist” is meant to include one or moreopioid antagonists, either alone or in combination, and is further meantto include partial antagonists, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers thereof, esters thereof, andcombinations thereof. The pharmaceutically acceptable salts includemetal salts, such as sodium salt, potassium salt, cesium salt, and thelike; alkaline earth metals, such as calcium salt, magnesium salt, andthe like; organic amine salts, such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, and the like;inorganic acid salts, such as hydrochloride, hydrobromide, sulfate,phosphate, and the like; organic acid salts, such as formate, acetate,trifluoroacetate, maleate, tartrate, and the like; sulfonates, such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts, such as arginate, asparginate, glutamate, and thelike. In certain embodiments, the amount of the opioid antagonist,present in sequestered form, can be about 10 ng to about 275 mg. In apreferred embodiment, when the antagonist is naltrexone, it ispreferable that the intact dosage form releases less than 0.125 mg orless within 24 hours, with 0.25 mg or greater of naltrexone releasedafter 1 hour when the dosage form is crushed or chewed.

In a preferred embodiment, the opioid antagonist comprises naloxone.Naloxone is an opioid antagonist, which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to block completely the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver, such that it has been reported to havesignificantly lower potency than when parenterally administered. Oraldosages of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours. It has been reported that 25% ofnaloxone administered sublingually is absorbed (Weinberg et al., Clin.Pharmacol. Ther. 44:335-340 (1988)).

In another preferred embodiment, the opioid antagonist comprisesnaltrexone. In the treatment of patients previously addicted to opioids,naltrexone has been used in large oral doses (over 100 mg) to preventeuphorigenic effects of opioid agonists. Naltrexone has been reported toexert strong preferential blocking action against mu over delta sites.Naltrexone is known as a synthetic congener of oxymorphone with noopioid agonist properties, and differs in structure from oxymorphone bythe replacement of the methyl group located on the nitrogen atom ofoxymorphone with a cyclopropylmethyl group. The hydrochloride salt ofnaltrexone is soluble in water up to about 100 mg/cc. Thepharmacological and pharmacokinetic properties of naltrexone have beenevaluated in multiple animal and clinical studies. See, e.g., Gonzalezet al. Drugs 35:192-213 (1988). Following oral administration,naltrexone is rapidly absorbed (within 1 hour) and has an oralbioavailability ranging from 5-40%. Naltrexone's protein binding isapproximately 21% and the volume of distribution following single-doseadministration is 16.1 L/kg.

Naltrexone is commercially available in tablet form (Revia®, DuPont(Wilmington, Del.)) for the treatment of alcohol dependence and for theblockade of exogenously administered opioids. See, e.g., Revia(naltrexone hydrochloride tablets), Physician's Desk Reference, 51′ ed.,Montvale, N.J.; and Medical Economics 51:957-959 (1997). A dosage of 50mg Revia® blocks the pharmacological effects of 25 mg IV administeredheroin for up to 24 hours. It is known that, when coadministered withmorphine, heroin or other opioids on a chronic basis, naltrexone blocksthe development of physical dependence to opioids. It is believed thatthe method by which naltrexone blocks the effects of heroin is bycompetitively binding at the opioid receptors. Naltrexone has been usedto treat narcotic addiction by complete blockade of the effects ofopioids. It has been found that the most successful use of naltrexonefor a narcotic addiction is with narcotic addicts having good prognosis,as part of a comprehensive occupational or rehabilitative programinvolving behavioral control or other compliance-enhancing methods. Fortreatment of narcotic dependence with naltrexone, it is desirable thatthe patient be opioid-free for at least 7-10 days. The initial dosage ofnaltrexone for such purposes has typically been about 25 mg, and if nowithdrawal signs occur, the dosage may be increased to 50 mg per day. Adaily dosage of 50 mg is considered to produce adequate clinicalblockade of the actions of parenterally administered opioids. Naltrexonealso has been used for the treatment of alcoholism as an adjunct withsocial and psychotherapeutic methods.

Other preferred opioid antagonists include, for example, cyclazocine andnaltrexone, both of which have cyclopropylmethyl substitutions on thenitrogen, retain much of their efficacy by the oral route, and lastlonger, with durations approaching 24 hours after oral administration.

The aversive agent of the present inventive sequestering subunit can bea bittering agent. The term “bittering agent” as used herein refers toany agent that provides an unpleasant taste to the host upon inhalationand/or swallowing of a tampered dosage form comprising the sequesteringsubunit. With the inclusion of a bittering agent in the sequesteringsubunit, the intake of the tampered dosage form produces a bitter tasteupon inhalation or oral administration, which, in certain embodiments,spoils or hinders the pleasure of obtaining a high from the tampereddosage form, and preferably prevents the abuse of the dosage form.

Various bittering agents can be employed including, for example, andwithout limitation, natural, artificial and synthetic flavor oils andflavoring aromatics and/or oils, oleoresins and extracts derived fromplants, leaves, flowers, fruits, and so forth, and combinations thereof.Nonlimiting representative flavor oils include spearmint oil, peppermintoil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitteralmonds, menthol and the like. Also useful bittering agents areartificial, natural and synthetic fruit flavors such as citrus oils,including lemon, orange, lime, and grapefruit, fruit essences, and soforth. Additional bittering agents include sucrose derivatives (e.g.,sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, andthe like. A preferred bittering agent for use in the invention isDenatonium Benzoate NF-Anhydrous, sold under the name Bitrex™ (MacfarlanSmith Limited, Edinburgh, UK).

A bittering agent can be added to the formulation in an amount of lessthan about 50% by weight, preferably less than about 10% by weight, morepreferably less than about 5% by weight of the dosage form, and mostpreferably in an amount ranging from about 0.1 to 1.0 percent by weightof the dosage form, depending on the particular bittering agent(s) used.

Alternatively, the aversive agent of the present inventive sequesteringsubunit can be a dye. The term “dye” as used herein refers to any agentthat causes discoloration of the tissue in contact. In this regard, ifthe sequestering subunit is tampered with and the contents are snorted,the dye will discolor the nasal tissues and surrounding tissues thereof.Preferred dyes are those that can bind strongly with subcutaneous tissueproteins and are well-known in the art. Dyes useful in applicationsranging from, for example, food coloring to tattooing, are exemplarydyes suitable for the invention. Food coloring dyes include, but are notlimited to FD&C Green #3 and FD&C Blue #1, as well as any other FD&C orD&C color. Such food dyes are commercially available through companies,such as Voigt Global Distribution (Kansas City, Mo.).

Alternatively, the aversive agent of the present inventive sequesteringsubunit can be a gelling agent. The term “gelling agent” as used hereinrefers to any agent that provides a gel-like quality to the tampereddosage form, which slows the absorption of the therapeutic agent, whichis formulated with the sequestering subunit, such that a host is lesslikely to obtain a rapid “high.” In certain preferred embodiments, whenthe dosage form is tampered with and exposed to a small amount (e.g.,less than about 10 ml) of an aqueous liquid (e.g., water), the dosageform will be unsuitable for injection and/or inhalation. Upon theaddition of the aqueous liquid, the tampered dosage form preferablybecomes thick and viscous, rendering it unsuitable for injection. Theterm “unsuitable for injection” is defined for purposes of the inventionto mean that one would have substantial difficulty injecting the dosageform (e.g., due to pain upon administration or difficulty pushing thedosage form through a syringe) due to the viscosity imparted on thedosage form, thereby reducing the potential for abuse of the therapeuticagent in the dosage form. In certain embodiments, the gelling agent ispresent in such an amount in the dosage form that attempts atevaporation (by the application of heat) to an aqueous mixture of thedosage form in an effort to produce a higher concentration of thetherapeutic agent, produces a highly viscous substance unsuitable forinjection. When nasally inhaling the tampered dosage form, the gellingagent can become gel-like upon administration to the nasal passages, dueto the moisture of the mucous membranes. This also makes suchformulations aversive to nasal administration, as the gel will stick tothe nasal passage and minimize absorption of the abusable substance.

Various gelling agents can be employed in the sequestering subunit ofthe invention, including, for example, and without limitation, sugars orsugar-derived alcohols, such as mannitol, sorbitol, and the like, starchand starch derivatives, cellulose derivatives, such as microcrystallinecellulose, sodium caboxymethyl cellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, andhydroxypropyl methylcellulose, attapulgites, bentonites, dextrins,alginates, carrageenan, gum tragacant, gum acacia, guar gum, xanthangum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, thecarbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol,polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants,mixed surfactant/wetting agent systems, emulsifiers, other polymericmaterials, and mixtures thereof; etc. In certain preferred embodiments,the gelling agent is xanthan gum. In other preferred embodiments, thegelling agent of the invention is pectin. The pectin or pecticsubstances useful for this invention include not only purified orisolated pectates but also crude natural pectin sources, such as apple,citrus or sugar beet residues, which have been subjected, whennecessary, to esterification or de-esterification, e.g., by alkali orenzymes. Preferably, the pectins used in this invention are derived fromcitrus fruits, such as lime, lemon, grapefruit, and orange.

With the inclusion of a gelling agent in the dosage form, the gellingagent preferably imparts a gel-like quality to the dosage form upontampering that spoils or hinders the pleasure of obtaining a rapid highfrom due to the gel-like consistency of the tampered dosage form incontact with the mucous membrane, and in certain embodiments, preventsthe abuse of the dosage form by minimizing absorption, e.g., in thenasal passages. A gelling agent can be added to the formulation in aratio of gelling agent to opioid agonist of from about 1:40 to about40:1 by weight, preferably from about 1:1 to about 30:1 by weight, andmore preferably from about 2:1 to about 10:1 by weight of the opioidagonist. In certain other embodiments, the dosage form forms a viscousgel having a viscosity of at least about 10 cP after the dosage form istampered with by dissolution in an aqueous liquid (from about 0.5 toabout 10 ml and preferably from 1 to about 5 ml). Most preferably, theresulting mixture will have a viscosity of at least about 60 cP.

The aversive agent of the present inventive sequestering subunit canalternatively be an irritant. The term “irritant” as used hereinincludes a compound used to impart an irritating, e.g., burning oruncomfortable, sensation to an abuser administering a tampered dosageform of the invention. Use of an irritant will discourage an abuser fromtampering with the dosage form and thereafter inhaling, injecting, orswallowing the tampered dosage form. Preferably, the irritant isreleased when the dosage form is tampered with and provides a burning orirritating effect to the abuser upon inhalation, injection, and/orswallowing the tampered dosage form.

Various irritants can be employed including, for example, and withoutlimitation, capsaicin, a capsaicin analog with similar type propertiesas capsaicin, and the like. Some capsaicin analogues or derivativesinclude, for example, and without limitation, resiniferatoxin,tinyatoxin, heptanoylisobutylamide, heptanoyl guaiacylamide, otherisobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyloctylester, nonanoyl vanillylamide, or other compounds of the classknown as vanilloids. Resiniferatoxin is described, for example, in U.S.Pat. No. 5,290,816. U.S. Pat. No. 4,812,446 describes capsaicin analogsand methods for their preparation. Furthermore, U.S. Pat. No. 4,424,205cites Newman, “Natural and Synthetic Pepper-Flavored Substances,”published in 1954 as listing pungency of capsaicin-like analogs. Ton etal., British Journal of Pharmacology 10:175-182 (1955), discussespharmacological actions of capsaicin and its analogs.

With the inclusion of an irritant (e.g., capsaicin) in the dosage form,the irritant imparts a burning or discomforting quality to the abuser todiscourage the inhalation, injection, or oral administration of thetampered dosage form, and preferably to prevent the abuse of the dosageform. Suitable capsaicin compositions include capsaicin (trans8-methyl-N-vanillyl-6-noneamide) or analogues thereof in a concentrationbetween about 0.00125% and 50% by weight, preferably between about 1%and about 7.5% by weight, and most preferably, between about 1% andabout 5% by weight.

The aversive agent can comprise a single type of aversive agent (e.g., acapsaicin), multiple forms of a single type of aversive agent (e.g., acapasin and an analogue thereof), or a combination of different types ofaversive agents (e.g., one or more bittering agents and one or moregelling agents). Desirably, the amount of aversive agent in thesequestering subunit of the invention is not toxic to the host.

The sequestering subunit of the invention can have a blocking agent thatis a tether to which the aversive agent is attached. The term “tether”as used herein refers to any means by which the aversive agent istethered or attached to the interior of the sequestering subunit, suchthat the aversive agent is not released, unless the sequestering subunitis tampered with. In this instance, a tether-aversive agent complex isformed. The complex is coated with a tether-impermeable material,thereby substantially preventing release of the aversive agent from thesubunit. The term “tether-impermeable material” as used herein refers toany material that substantially prevents or prevents the tether frompermeating through the material. The tether preferably is an ionexchange resin bead.

Methods of making any of the sequestering subunits of the invention areknown in the art. See, for example, Remington: The Science and Practiceof Pharmacy, Alfonso R. Genaro (ed), 20^(th) edition, and Example 2 setforth below. The sequestering subunits can be prepared by any suitablemethod to provide, for example, beads, pellets, granules, spheroids, andthe like.

Spheroids or beads, coated with an active ingredient can be prepared,for example, by dissolving the active ingredient in water and thenspraying the solution onto a substrate, for example, nu pariel 18/20beads, using a Wurster insert. Optionally, additional ingredients arealso added prior to coating the beads in order to assist the activeingredient in binding to the substrates, and/or to color the solution;etc. The resulting substrate-active material optionally can beovercoated with a barrier material to separate the therapeuticallyactive agent from the next coat of material, e.g., release-retardingmaterial. Preferably, the barrier material is a material comprisinghydroxypropyl methylcellulose. However, any film-former known in the artcan be used. Preferably, the barrier material does not affect thedissolution rate of the final product.

Pellets comprising an active ingredient can be prepared, for example, bya melt pelletization technique. Typical of such techniques is when theactive ingredient in finely divided form is combined with a binder (alsoin particulate form) and other optional inert ingredients, andthereafter the mixture is pelletized, e.g., by mechanically working themixture in a high shear mixer to form the pellets (e.g., pellets,granules, spheres, beads; etc., collectively referred to herein as“pellets”). Thereafter, the pellets can be sieved in order to obtainpellets of the requisite size. The binder material is preferably inparticulate form and has a melting point above about 40° C. Suitablebinder substances include, for example, hydrogenated castor oil,hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols,fatty acid esters, fatty acid glycerides, and the like.

The diameter of the extruder aperture or exit port also can be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular;etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine; etc.

The melt-extruded multiparticulate system can be, for example, in theform of granules, spheroids, pellets, or the like, depending upon theextruder exit orifice. The terms “melt-extruded multiparticulate(s)” and“melt-extruded multiparticulate system(s)” and “melt-extruded particles”are used interchangeably herein and include a plurality of subunits,preferably within a range of similar size and/or shape. Themelt-extruded multiparticulates are preferably in a range of from about0.1 to about 12 mm in length and have a diameter of from about 0.1 toabout 5 mm. In addition, the melt-extruded multiparticulates can be anygeometrical shape within this size range. Alternatively, the extrudatecan simply be cut into desired lengths and divided into unit doses ofthe therapeutically active agent without the need of a spheronizationstep.

The substrate also can be prepared via a granulation technique.Generally, melt-granulation techniques involve melting a normally solidhydrophobic material, e.g., a wax, and incorporating an activeingredient therein. To obtain a sustained-release dosage form, it can benecessary to incorporate an additional hydrophobic material.

A coating composition can be applied onto a substrate by spraying itonto the substrate using any suitable spray equipment. For example, aWuster fluidized-bed system can be used in which an air flow fromunderneath, fluidizes the coated material and effects drying, while theinsoluble polymer coating is sprayed on. The thickness of the coatingwill depend on the characteristics of the particular coatingcomposition, and can be determined by using routine experimentation.

Any manner of preparing a subunit can be employed. By way of example, asubunit in the form of a pellet or the like can be prepared byco-extruding a material comprising the opioid agonist and a materialcomprising the opioid antagonist and/or aversive agent in sequesteredform. Optionally, the opioid agonist composition can cover, e.g.,overcoat, the material comprising the antagonist and/or aversive agentin sequestered form. A bead, for example, can be prepared by coating asubstrate comprising an opioid antagonist and/or an aversive agent insequestered form with a solution comprising an opioid agonist.

The sequestering subunits of the invention are particularly well-suitedfor use in compositions comprising the sequestering subunit and atherapeutic agent in releasable form. In this regard, the invention alsoprovides a composition comprising any of the sequestering subunits ofthe invention and a therapeutic agent in releasable form. By “releasableform” is meant to include immediate release, intermediate release, andsustained-release forms. The therapeutic agent can be formulated toprovide immediate release of the therapeutic agent. In preferredembodiments, the composition provides sustained-release of thetherapeutic agent.

The therapeutic agent in sustained-release form is preferably a particleof therapeutic agent that is combined with a release-retarding material.The release-retarding material is preferably a material that permitsrelease of the therapeutic agent at a sustained rate in an aqueousmedium. The release-retarding material can be selectively chosen so asto achieve, in combination with the other stated properties, a desiredin vitro release rate.

In a preferred embodiment, the oral dosage form of the invention can beformulated to provide for an increased duration of therapeutic actionallowing once-daily dosing. In general, a release-retarding material isused to provide the increased duration of therapeutic action.Preferably, the once-daily dosing is provided by the dosage forms andmethods described in U.S. patent application Ser. No. (unknown) toBoehm, entitled “Sustained-Release Opioid Formulations and Method ofUse,” filed on Sep. 22, 2003, and incorporated herein by reference.

Preferred release-retarding materials include acrylic polymers,alkylcelluloses, shellac, zein, hydrogenated vegetable oil, hydrogenatedcastor oil, and combinations thereof. In certain preferred embodiments,the release-retarding material is a pharmaceutically acceptable acrylicpolymer, including acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cynaoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), poly(methacrylic acid anhydride), methylmethacrylate, polymethacrylate, poly(methyl methacrylate) copolymer,polyacrylamide, aminoalkyl methacrylate copolymer, and glycidylmethacrylate copolymers. In certain preferred embodiments, the acrylicpolymer comprises one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well-known in the art, and are described inNF21, the 21^(st) edition of the National Formulary, published by theUnited States Pharmacopeial Convention Inc. (Rockville, Md.), as fullypolymerized copolymers of acrylic and methacrylic acid esters with a lowcontent of quaternary ammonium groups. In other preferred embodiments,the release-retarding material is an alkyl cellulosic material, such asethylcellulose. Those skilled in the art will appreciate that othercellulosic polymers, including other alkyl cellulosic polymers, can besubstituted for part or all of the ethylcellulose.

Release-modifying agents, which affect the release properties of therelease-retarding material, also can be used. In a preferred embodiment,the release-modifying agent functions as a pore-former. The pore-formercan be organic or inorganic, and include materials that can bedissolved, extracted or leached from the coating in the environment ofuse. The pore-former can comprise one or more hydrophilic polymers, suchas hydroxypropylmethylcellulose. In certain preferred embodiments, therelease-modifying agent is selected from hydroxypropylmethylcellulose,lactose, metal stearates, and combinations thereof.

The release-retarding material can also include an erosion-promotingagent, such as starch and gums; a release-modifying agent useful formaking microporous lamina in the environment of use, such aspolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups reoccur in the polymer chain; and/or a semi-permeablepolymer.

The release-retarding material can also include an exit means comprisingat least one passageway, orifice, or the like. The passageway can beformed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770;3,916,889; 4,063,064; and 4,088,864, which are incorporated herein byreference. The passageway can have any shape, such as round, triangular,square, elliptical, irregular; etc.

In certain embodiments, the therapeutic agent in sustained-release formcan include a plurality of substrates comprising the active ingredient,which substrates are coated with a sustained-release coating comprisinga release-retarding material.

The sustained-release preparations of the invention can be made inconjunction with any multiparticulate system, such as beads,ion-exchange resin beads, spheroids, microspheres, seeds, pellets,granules, and other multiparticulate systems in order to obtain adesired sustained-release of the therapeutic agent. The multiparticulatesystem can be presented in a capsule or in any other suitable unitdosage form.

In certain preferred embodiments, more than one multiparticulate systemcan be used, each exhibiting different characteristics, such as pHdependence of release, time for release in various media (e.g., acid,base, simulated intestinal fluid), release in vivo, size andcomposition.

To obtain a sustained-release of the therapeutic agent in a mannersufficient to provide a therapeutic effect for the sustained durations,the therapeutic agent can be coated with an amount of release-retardingmaterial sufficient to obtain a weight gain level from about 2 to about30%, although the coat can be greater or lesser depending upon thephysical properties of the particular therapeutic agent utilized and thedesired release rate, among other things. Moreover, there can be morethan one release-retarding material used in the coat, as well as variousother pharmaceutical excipients.

Solvents typically used for the release-retarding material includepharmaceutically acceptable solvents, such as water, methanol, ethanol,methylene chloride and combinations thereof.

In certain embodiments of the invention, the release-retarding materialis in the form of a coating comprising an aqueous dispersion of ahydrophobic polymer. The inclusion of an effective amount of aplasticizer in the aqueous dispersion of hydrophobic polymer willfurther improve the physical properties of the film. For example,because ethylcellulose has a relatively high glass transitiontemperature and does not form flexible films under normal coatingconditions, it is necessary to plasticize the ethylcellulose beforeusing the same as a coating material. Generally, the amount ofplasticizer included in a coating solution is based on the concentrationof the film-former, e.g., most often from about 1 to about 50 percent byweight of the film-former. Concentrations of the plasticizer, however,can be determined by routine experimentation.

Examples of plasticizers for ethylcellulose and other celluloses includedibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate,and triacetin, although it is possible that other plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil; etc.) can beused.

Examples of plasticizers for the acrylic polymers include citric acidesters, such as triethyl citrate NF21, tributyl citrate, dibutylphthalate, and possibly 1,2-propylene glycol, polyethylene glycols,propylene glycol, diethyl phthalate, castor oil, and triacetin, althoughit is possible that other plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil; etc.) can be used.

The sustained-release profile of drug release in the formulations of theinvention (either in vivo or in vitro) can be altered, for example, byusing more than one release-retarding material, varying the thickness ofthe release-retarding material, changing the particularrelease-retarding material used, altering the relative amounts ofrelease-retarding material, altering the manner in which the plasticizeris added (e.g., when the sustained-release coating is derived from anaqueous dispersion of hydrophobic polymer), by varying the amount ofplasticizer relative to retardant material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture; etc.

In certain other embodiments, the oral dosage form can utilize amultiparticulate sustained-release matrix.

In certain embodiments, the sustained-release matrix comprises ahydrophilic and/or hydrophobic polymer, such as gums, cellulose ethers,acrylic resins and protein-derived materials. Of these polymers, thecellulose ethers, specifically hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form can containbetween about 1% and about 80% (by weight) of at least one hydrophilicor hydrophobic polymer.

The hydrophobic material is preferably selected from the groupconsisting of alkylcellulose, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. Preferably, the hydrophobic materialis a pharmaceutically acceptable acrylic polymer, including acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylicacid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial can also include hydrooxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophobic trends. Preferably, the hydrophobic material hasa melting point from about 30° C. to about 200° C., more preferably fromabout 45° C. to about 90° C. The hydrophobic material can includeneutral or synthetic waxes, fatty alcohols (such as lauryl, myristyl,stearyl, cetyl or preferably cetostearyl alcohol), fatty acids,including fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicacid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include beeswax, glycowax, castorwax, carnauba wax and wax-like substances, e.g., material normally solidat room temperature and having a melting point of from about 30° C. toabout 100° C.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably a natural or synthetic wax, afatty acid, a fatty alcohol, or mixtures thereof. Examples includebeeswax, carnauba wax, stearic acid and stearyl alcohol.

In other embodiments, the sustained-release matrix comprises digestible,long-chain (e.g., C₈-C₅₀, preferably C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between about 25° C. and about90° C. are preferred. Of these long-chain hydrocarbon materials, fatty(aliphatic) alcohols are preferred. The oral dosage form can contain upto about 60% (by weight) of at least one digestible, long-chainhydrocarbon.

Further, the sustained-release matrix can contain up to 60% (by weight)of at least one polyalkylene glycol.

In a preferred embodiment, the matrix comprises at least onewater-soluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁-C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, preferably, hydroxyethyl cellulose.The amount of the at least one hydroxyalkyl cellulose in the oral dosageform will be determined, amongst other things, by the precise rate ofopioid release required. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined by theprecise rate of opioid release required. However, it will also depend onwhether the at least one polyalkylene glycol is absent from the oraldosage form.

In certain embodiments, a spheronizing agent, together with the activeingredient, can be spheronized to form spheroids. Microcrystallinecellulose and hydrous lactose impalpable are examples of such agents.Additionally (or alternatively), the spheroids can contain awater-insoluble polymer, preferably an acrylic polymer, an acryliccopolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethylcellulose. In such embodiments, the sustained-release coating willgenerally include a water-insoluble material such as (a) a wax, eitheralone or in admixture with a fatty alcohol, or (b) shellac or zein.

Preferably, the sequestering subunit comprises the therapeutic agent insustained-release form. The sustained-release subunit can be prepared byany suitable method. For example, a plasticized aqueous dispersion ofthe release-retarding material can be applied onto the subunitcomprising the opioid agonist. A sufficient amount of the aqueousdispersion of release-retarding material to obtain a predeterminedsustained-release of the opioid agonist when the coated substrate isexposed to aqueous solutions, e.g., gastric fluid, is preferablyapplied, taking into account the physical characteristics of the opioidagonist, the manner of incorporation of the plasticizer; etc.Optionally, a further overcoat of a film-former, such as Opadry(Colorcon, West Point, Va.), can be applied after coating with therelease-retarding material.

The subunit can be cured in order to obtain a stabilized release rate ofthe therapeutic agent. In embodiments employing an acrylic coating, astabilized product can be preferably obtained by subjecting the subunitto oven curing at a temperature above the glass transition temperatureof the plasticized acrylic polymer for the required time period. Theoptimum temperature and time for the particular formulation can bedetermined by routine experimentation.

Once prepared, the subunit can be combined with at least one additionalsubunit and, optionally, other excipients or drugs to provide an oraldosage form.

In addition to the above ingredients, a sustained-release matrix alsocan contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Optionally and preferably, the mechanical fragility of any of thesequestering subunits described herein is the same as the mechanicalfragility of the therapeutic agent in releasable form. In this regard,tampering with the composition of the invention in a manner to obtainthe therapeutic agent will result in the destruction of the sequesteringsubunit, such that the aversive agent is released and mixed in with thetherapeutic agent. Consequently, the aversive agent cannot be separatedfrom the therapeutic agent, and the therapeutic agent cannot beadministered in the absence of the aversive agent. Methods of assayingthe mechanical fragility of the sequestering subunit and of atherapeutic agent are known in the art. See, for example, Example 3 setforth below.

The therapeutic agent of the present inventive compositions can be anymedicinal agent used for the treatment of a condition or disease, apharmaceutically acceptable salt thereof, or an analogue of either ofthe foregoing. The therapeutic agent can be, for example, an analgesic(e.g., an opioid agonist, aspirin, acetaminophen, non-steroidalanti-inflammatory drugs (“NSAIDS”), N-methyl-D-aspartate (“NMDA”)receptor antagonists, cyclooxygenase-II inhibitors (“COX-IIinhibitors”), and glycine receptor antagonists), an antibacterial agent,an anti-viral agent, an anti-microbial agent, anti-infective agent, achemotherapeutic, an immunosuppressant agent, an antitussive, anexpectorant, a decongestant, an antihistamine drugs, a decongestant,antihistamine drugs, and the like. Preferably, the therapeutic agent isone that is addictive (physically and/or psychologically) upon repeateduse and typically leads to abuse of the therapeutic agent. In thisregard, the therapeutic agent can be any opioid agonist as discussedherein.

Exemplary NSAIDS include ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam or isoxicam, and the like. Useful dosages of thesedrugs are well-known.

Exemplary NMDA receptor antagonists include morphinans, such asdexotromethorphan or dextrophan, ketamine, d-methadone, andpharmaceutically acceptable salts thereof, and encompass drugs thatblock a major intracellular consequence of NMDA-receptor activation,e.g., a ganglioside, such as(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics, such as morphine, codeine;etc., in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer et al.),both of which are incorporated herein by reference, and to treat chronicpain in U.S. Pat. No. 5,502,058 (Mayer et al.), incorporated herein byreference. The NMDA agonist can be included alone or in combination witha local anesthetic, such as lidocaine, as described in these patents byMayer et al.

COX-2 inhibitors have been reported in the art, and many chemicalcompounds are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422, 5,510,368; 5,436,265; 5,409,944 and5,130,311, all of which are incorporated herein by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2-naphthylacetic acid(6-NMA), MK-966 (also known as Vioxx), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614, or combinations thereof.Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg toabout 140 mg per kilogram of body weight per day have been shown to betherapeutically effective in combination with an opioid analgesic.Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2inhibitor can be administered in combination with an opioid analgesic.

The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber et al.), which is incorporated herein byreference.

Pharmaceutically acceptable salts of the therapeutic agents discussedherein include metal salts, such as sodium salt, potassium salt, cesiumsalt, and the like; alkaline earth metals, such as calcium salt,magnesium salt, and the like; organic amine salts, such as triethylaminesalt, pyridine salt, picoline salt, ethanolamine salt, triethanolaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamin-e salt, andthe like; inorganic acid salts, such as hydrochloride, hydrobromide,sulfate, phosphate, and the like; organic acid salts, such as formate,acetate, trifluoroacetate, maleate, tartrate, and the like; sulfonates,such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts, such as arginate, asparginate, glutamate, andthe like.

The composition of the invention can contain more than one therapeuticagent to provide a substantially equivalent therapeutic effect.Alternatively, the dosage form can contain molar equivalent amounts ofother salts of the therapeutic agents useful in the invention. By way ofexample, a combination of two opioid agonists can be included in thedosage form. Thus, in certain embodiments, a combination of two opioidagonists can be included in the same subunit, in addition to the opioidantagonist and/or aversive agent. For example, the subunit can includetwo opioid agonists having different properties, such as half-life,solubility, potency, and a combination of any of the foregoing. Further,the dosage form can include subunits comprising different opioidagonists or the subunits can be dispersed in a matrix comprisingdifferent opioid agonists. In further embodiments, the oral dosage formcomprises an opioid agonist and an aversive agent in sequestered form,and, optionally, an opioid antagonist in sequestered form, wherein theaversive agent and opioid agonist are not part of the same subunit.

The composition of the invention can be in any suitable dosage form orformulation, (see, e.g., Pharmaceutics and Pharmacy Practice, J. B.Lippincott Company, Philadelphia, Pa., Banker and Chalmers, eds., pages238-250 (1982)).

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of the inhibitor dissolved indiluents, such as water, saline, or orange juice; (b) capsules, sachets,tablets, lozenges, and troches, each containing a predetermined amountof the active ingredient, as solids or granules; (c) powders; (d)suspensions in an appropriate liquid; and (e) suitable emulsions. Liquidformulations may include diluents, such as water and alcohols, forexample, ethanol, benzyl alcohol, and the polyethylene alcohols, eitherwith or without the addition of a pharmaceutically acceptablesurfactant. Capsule forms can be of the ordinary hard- or soft-shelledgelatin type containing, for example, surfactants, lubricants, and inertfillers, such as lactose, sucrose, calcium phosphate, and corn starch.Tablet forms can include one or more of lactose, sucrose, mannitol, cornstarch, potato starch, alginic acid, microcrystalline cellulose, acacia,gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium,talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid,and other excipients, colorants, diluents, buffering agents,disintegrating agents, moistening agents, preservatives, flavoringagents, and pharmacologically compatible excipients. Lozenge forms cancomprise the active ingredient in a flavor, usually sucrose and acaciaor tragacanth, as well as pastilles comprising the active ingredient inan inert base, such as gelatin and glycerin, or sucrose and acacia,emulsions, gels, and the like containing, in addition to the activeingredient, such excipients as are known in the art.

One of ordinary skill in the art will readily appreciate that thecompositions of the invention can be modified in any number of ways,such that the therapeutic efficacy of the composition is increasedthrough the modification. For instance, the therapeutic agent orsequestering subunit could be conjugated either directly or indirectlythrough a linker to a targeting moiety. The practice of conjugatingtherapeutic agents or sequestering subunits to targeting moieties isknown in the art. See, for instance, Wadwa et al., J. Drug Targeting 3:111 (1995), and U.S. Pat. No. 5,087,616. The term “targeting moiety” asused herein, refers to any molecule or agent that specificallyrecognizes and binds to a cell-surface receptor, such that the targetingmoiety directs the delivery of the therapeutic agent or sequesteringsubunit to a population of cells on which the receptor is expressed.Targeting moieties include, but are not limited to, antibodies, orfragments thereof, peptides, hormones, growth factors, cytokines, andany other naturally- or non-naturally-existing ligands, which bind tocell-surface receptors. The term “linker” as used herein, refers to anyagent or molecule that bridges the therapeutic agent or sequesteringsubunit to the targeting moiety. One of ordinary skill in the artrecognizes that sites on the therapeutic agent or sequestering subunit,which are not necessary for the function of the agent or sequesteringsubunit, are ideal sites for attaching a linker and/or a targetingmoiety, provided that the linker and/or targeting moiety, once attachedto the agent or sequestering subunit, do(es) not interfere with thefunction of the therapeutic agent or sequestering subunit.

With respect to the present inventive compositions, the composition ispreferably an oral dosage form. By “oral dosage form” is meant toinclude a unit dosage form prescribed or intended for oraladministration comprising subunits. Desirably, the composition comprisesthe sequestering subunit coated with the therapeutic agent in releasableform, thereby forming a composite subunit comprising the sequesteringsubunit and the therapeutic agent. Accordingly, the invention furtherprovides a capsule suitable for oral administration comprising aplurality of such composite subunits.

Alternatively, the oral dosage form can comprise any of the sequesteringsubunits of the invention in combination with a therapeutic agentsubunit, wherein the therapeutic agent subunit comprises the therapeuticagent in releasable form. In this respect, the invention provides acapsule suitable for oral administration comprising a plurality ofsequestering subunits of the invention and a plurality of therapeuticsubunits, each of which comprises a therapeutic agent in releasableform.

The invention further provides tablets comprising a sequestering subunitof the invention and a therapeutic agent in releasable form. Forinstance, the invention provides a tablet suitable for oraladministration comprising a first layer comprising any of thesequestering subunits of the invention and a second layer comprisingtherapeutic agent in releasable form, wherein the first layer is coatedwith the second layer. The first layer can comprise a plurality ofsequestering subunits. Alternatively, the first layer can be or canconsist of a single sequestering subunit. The therapeutic agent inreleasable form can be in the form of a therapeutic agent subunit andthe second layer can comprise a plurality of therapeutic subunits.Alternatively, the second layer can comprise a single substantiallyhomogeneous layer comprising the therapeutic agent in releasable form.

The invention further provides a tablet suitable for oral administrationcomprising a single layer comprising a therapeutic agent in releasableform and a plurality of any of the sequestering subunits of theinvention dispersed throughout the layer of the therapeutic agent inreleasable form. The invention also provides a tablet in which thetherapeutic agent in releasable form is in the form of a therapeuticagent subunit and the tablet comprises an at least substantiallyhomogeneous mixture of a plurality of sequestering subunits and aplurality of subunits comprising the therapeutic agent.

In preferred embodiments, oral dosage forms are prepared to include aneffective amount of melt-extruded subunits in the form of multiparticleswithin a capsule. For example, a plurality of the melt-extrudedmultiparticulates can be placed in a gelatin capsule in an amountsufficient to provide an effective release dose when ingested andcontacted by gastric fluid.

In another preferred embodiment, the subunits, e.g., in the form ofmultiparticulates, can be compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Aurther Osol., editor), 1553-1593 (1980),which is incorporated herein by reference. Excipients in tabletformulation can include, for example, an inert diluent such as lactose,granulating and disintegrating agents, such as cornstarch, bindingagents, such as starch, and lubricating agents, such as magnesiumstearate.

In yet another preferred embodiment, the subunits are added during theextrusion process and the extrudate can be shaped into tablets as setforth in U.S. Pat. No. 4,957,681 (Klimesch et al.), which isincorporated herein by reference.

Optionally, the sustained-release, melt-extruded, multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained-release coating, such as the sustained-releasecoatings described herein. Such coatings are particularly useful whenthe subunit comprises an opioid agonist in releasable form, but not insustained-release form. The coatings preferably include a sufficientamount of a hydrophobic material to obtain a weight gain level formabout 2 to about 30 percent, although the overcoat can be greater,depending upon the physical properties of the particular opioidanalgesic utilized and the desired release rate, among other things.

The melt-extruded dosage forms can further include combinations ofmelt-extruded multiparticulates containing one or more of thetherapeutically active agents before being encapsulated. Furthermore,the dosage forms can also include an amount of an immediate releasetherapeutic agent for prompt therapeutic effect. The immediate releasetherapeutic agent can be incorporated or coated on the surface of thesubunits after preparation of the dosage forms (e.g., controlled-releasecoating or matrix-based). The dosage forms can also contain acombination of controlled-release beads and matrix multiparticulates toachieve a desired effect.

The sustained-release formulations preferably slowly release thetherapeutic agent, e.g., when ingested and exposed to gastric fluids,and then to intestinal fluids. The sustained-release profile of themelt-extruded formulations can be altered, for example, by varying theamount of retardant, e.g., hydrophobic material, by varying the amountof plasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture; etc.

In other embodiments, the melt-extruded material is prepared without theinclusion of the subunits, which are added thereafter to the extrudate.Such formulations can have the subunits and other drugs blended togetherwith the extruded matrix material, and then the mixture is tableted inorder to provide a slow release of the therapeutic agent or other drugs.Such formulations can be particularly advantageous, for example, whenthe therapeutically active agent included in the formulation issensitive to temperatures needed for softening the hydrophobic materialand/or the retardant material.

In certain embodiments, the release of the aversive agent of thesequestering subunit or composition is expressed in terms of a ratio ofthe release achieved after tampering, e.g., by crushing or chewing,relative to the amount released from the intact formulation. The ratiois, therefore, expressed as [Crushed]:[Whole], and it is desired thatthis ratio have a numerical range of at least about 4:1 or greater(e.g., crushed release within 1 hour/intact release in 24 hours). Incertain embodiments, the ratio of the therapeutic agent and the aversiveagent, present in the sequestering subunit, is about 1:1 to about 50:1by weight, preferably about 1:1 to about 20:1 by weight or 15:1 to about30:1 by weight. The weight ratio of the therapeutic agent to aversiveagent refers to the weight of the active ingredients. Thus, for example,the weight of the therapeutic agent excludes the weight of the coating,matrix, or other component that renders the aversive agent sequestered,or other possible excipients associated with the aversive agentparticles. In certain preferred embodiments, the ratio is about 1:1 toabout 10:1 by weight. Because in certain embodiments the aversive agentis in a sequestered from, the amount of such aversive agent within thedosage form can be varied more widely than the therapeuticagent/aversive agent combination dosage forms, where both are availablefor release upon administration, as the formulation does not depend ondifferential metabolism or hepatic clearance for proper functioning. Forsafety reasons, the amount of the aversive agent present in asubstantially non-releasable form is selected as not to be harmful tohumans, even if fully released under conditions of tampering.

The compositions of the invention are particularly well-suited for usein preventing abuse of a therapeutic agent. In this regard, theinvention also provides a method of preventing abuse of a therapeuticagent by a host. The method comprises incorporating the therapeuticagent into any of the compositions of the invention. Upon administrationof the composition of the invention to the host, the aversive agent issubstantially prevented from being released in the gastrointestinaltract for a time period that is greater than 24 hours. However, if thehost tampers with the compositions, the sequestering subunit, which ismechanically fragile, will break and thereby allow the aversive agent tobe released. Since the mechanical fragility of the sequestering subunitis the same as the therapeutic agent in releasable form, the aversiveagent will be mixed with the therapeutic agent, such that separationbetween the two components is virtually impossible.

The term “host” as used herein refers to any suitable host. Preferably,the host is a mammal. An especially preferred mammal is the human.

EXAMPLES

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

Example 1

This example demonstrates multiple sequestered forms of aversive agentsof the prior art and how they release substantial amounts of theaversive agent within a 24 hour time period.

A first sequestered form of an aversive agent comprised the followingcomponents:

Core Formulation:

Naltrexone HCl  70.0 g Methocel E5P  5.0 g Sugar spheres (#16-18 mesh)700.0 g Ethyl Alcohol (denatured, SDA3A) 200.0 g Purified Water 200.0 g

Film-Coating Formulation:

Eudragit RS100  140.0 g Triethyl Citrate (TEC)  14.0 g Ethyl Alcohol1260.0 g

Naltrexone HCl was dissolved in water. An equal volume of denaturedalcohol was added. Methocel was added to the above mixture and stirreduntil it was completely dissolved. The drug layering took place in arotor processor insert installed in fluid-bed equipment. A coatingsolution was prepared by dissolving the Eudragit RS100 in Ethyl Alcoholand dissolving the triethyl citrate in the solution. The naltrexonecores (700 g) were than coated with the coating solution up to a 20%weight gain. The coating was performed in a fluid-bed equipped with aWurster insert.

The release of naltrexone was determined by dissolution testingconducted according to USP26 Chapter <711>. The test used Apparatus 1(baskets) at 50 rpm, 500 mL of water, 37° C. Samples were drawn andassayed by a HPLC assay procedure. The HPLC assay procedure was asfollows.

Column: Symmetry Shield RP8, 5 micron, 4.6 × 150 mm Column Temperature:55° C. Mobile Phase: 0.1M ammonium acetate pH 5.0/acetonitrile 880/120Flow Rate: 1.0 mL/minute Injection Volume: 50 μl Detection: UV at 281 nm

As shown in Table 1, the release of naltrexone from a sequesteringsubunit comprising 20% weight gain of Eudragit RS100/TEC was inhibitedto the same extent as the release of naltrexone from a sequesteringsubunit comprising 16% weight gain of Eudragit RS100/TEC. Specifically,more than 20% of the starting dose of naltrexode was released fromeither sequestering subunit after 24 hours had elapsed. This indicatesthat the sequestering unit is unable to substantially prevent therelease of the Naltrexone over 24 hours.

TABLE 1 % release at indicated timepoint (hours) Time (hours) 5 10 15 2024 16% weight gain 3.3 6.3 10.8 16.4 20.9 20% weight gain 7.2 12.3 17.922.9 26.5

A second sequestered form of an aversive agent comprised the followingcomponents:

Core Formulation:

Naltrexone HCl  70.0 g Methocel E5P  5.0 g Sugar spheres (#16-18 mesh)700.0 g Ethyl alcohol (denatured, SDA3A) 200.0 g Purified Water 200.0 g

Film-Coating Formulation:

Eudragit NE 30D 500.0 g Triethyl Citrate (TEC) 150.0 g Ethyl Alcohol1260.0 g 

The sequestering subunit was made by the same process as the firstsequestering subunit. The release of naltrexone was assayed in the samemanner as above.

As shown in Table 2, the release of naltrexone from a sequesteringsubunit comprising 20% weight gain of Eudragit NE30D/TEC was inhibitedto a similar extent as the release of naltrexone from a sequesteringsubunit comprising 16% weight gain of Eudragit NE30D/TEC. Specifically,about 80% of the starting dose of naltrexone was released from eithersequestering subunit after 20 hours had elapsed. This indicates that thesequestering unit is unable to substantially prevent the release of theNaltrexone over 24 hours.

TABLE 2 % release at indicated timepoint (hours) Time (hours) 5 10 15 2024 16% weight gain 60 76.5 83.5 82.9 N/D 20% weight gain 48.3 69.1 78.578.7 N/D N/D = not determined

A third sequestered form of an aversive agent comprised the followingcomponents:

Core Formulation:

Naltrexone HCl  70.0 g Methocel E5P  5.0 g Sugar spheres (#16-18 mesh)700.0 g Ethyl Alcohol (denatured, SDA3A) 200.0 g Purified Water 200.0 g

Film-Coating Formulation:

Ethyl Cellulose N10  126.0 g Dibutyl Sebacate (DBS)  14.0 g EthylAlcohol 1260.0 g

The sequestering subunit was made in accordance with the above method.The release of naltrexone was also assayed in the same manner as above.

As shown in Table 3, 100% of the starting dose of naltrexone wasreleased from the sequestering subunit after 20 hours had elapsed. Thepercentage weight gain did not significantly affect the release ofnaltrexone. This indicates that the sequestering unit is unable tosubstantially prevent the release of the Naltrexone over 24 hours.

TABLE 3 % release at indicated timepoint (hours) Time (hours) 5 10 15 2024 12% weight gain 39.0 60.3 77.9 99.6 N/D 16% weight gain 36.4 60.180.5 108.8 N/D 20% weight gain 29.2 52.3 71.1 95.7 N/D N/D = notdetermined

A fourth sequestered form of an aversive agent comprised the followingcomponents:

Core Formulation:

Naltrexone HCl 115.0 g Plasdone K29/32 115.0 g Sugar spheres (18-20mesh) 1930.0 g  Ethyl Alcohol 651.0 g Purified Water 651.0 g

Film-Coating Formulation:

Eudragit RS100  189.0 g Dibutyl Sebacate  21.0 g Ethyl Alcohol 2590.0 g

The sequestering subunit was made in accordance with the above method.The release of naltrexone was also assayed in the same manner as above.

As shown in Table 4, coatings that provided a 25% weight gain of thesequestering subunit demonstrated the least amount of release ofnaltrexone. Specifically, 23.3% of the starting amount was released in24 hours. In contrast, the sequestering subunit comprising a coating,which provided a 12% weight gain, released about 90% of the startingamount of naltrexone. This indicates that the sequestering unit isunable to substantially prevent the release of the naltrexone over 24hours at any of these applied coat weights. Even at 25% weight gain, thesequestering subunit is unable to prevent the release of more than 20%of the Naltrexone at 24 hours.

TABLE 4 % release at indicated timepoint (hours) Time (hours) 5 10 15 2024 12% weight gain 27.3 58.9 75.0 84.7 89.7 16% weight gain 11.6 32.148.2 31.2 70.0 20% weight gain 5.2 20.3 27.5 35.2 43.4 25% weight gain2.5 12.8 17.0 20.2 23.3

A fifth sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Caffeine 5.0 Sugar Spheres (#16-18 mesh) 94.6Hypromellose 0.4 Ethylcellulose 7.9 Dibutyl Sebacate 1.6 MagnesiumStearate 1.6 Total 111.1

Caffeine was dispersed in a hydroalcoholic solution of hypromellose witha mechanical stirrer. The resulting dispersion was layered onto sugarspheres using a rotor granulation process in Glatt GPCG-3 fluid-bed. Apolymer solution of ethylcellulose and dibutyl sebacate in ethanol wasprepared, and magnesium stearate was dispersed into the polymer solutionjust prior to spraying. The polymer dispersion was then coated ontocaffeine cores in Glatt GPCG-3 with a 4″ Wurster insert.

The release of caffeine was determined by dissolution testing conductedaccording to USP26 Chapter <711>. The test used Apparatus 2 (paddles) at100 rpm, 900 mL of 0.05M phosphate buffer pH 7.5, 37° C. Samples weredrawn and assayed UV absorbance at 273 nm.

As shown in Table 5 (set forth below), 50% of the starting dose ofcaffeine was released after 10 hours, whereas over 80% of the startingdose of caffeine was released after 17 hours had elapsed. This indicatesthat the sequestering unit is unable to substantially prevent therelease of the caffeine over 24 hours.

A sixth sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Caffeine 5.0 Sugar Spheres (#16-18 mesh) 94.6Hypromellose 0.4 Eudragit RS PO 8.1 Sodium Lauryl Sulfate 0.2 DibutylSebacate 0.8 Magnesium Stearate 2.0 Total 111.1

Caffeine was dispersed in a hydroalcoholic solution of hypromellose witha mechanical stirrer. The resulting dispersion was layered onto sugarspheres using a rotor granulation process in Glatt GPCG-3 fluid-bed. Apolymer solution of Eudragit RS, sodium lauryl sulfate and dibutylsebacate in ethanol was prepared, and magnesium stearate was dispersedinto the polymer solution just prior to spraying. The polymer dispersionwas then coated onto caffeine cores in Glatt GPCG-3 with a 4″ Wursterinsert. The release of caffeine was assayed as described above.

As shown in Table 5, 46% of the starting dose of caffeine was releasedafter 13 hours, whereas over 60% of the starting dose of caffeine wasreleased after 17 hours had elapsed. This indicates that thesequestering unit is unable to substantially prevent the release of thecaffeine over 24 hours.

A seventh sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Caffeine 5.0 Sugar Spheres (#16-18 mesh) 94.5Hydroxypropyl Cellulose 0.5 Ethylcellulose 9.6 Dibutyl Sebacate 1.5Total 111.1

Caffeine was dispersed in an ethanolic solution of hydroxypropylcellulose using a mechanical stirrer. The resulting dispersion waslayered onto sugar spheres using a rotor granulation process in GlattGPCG-3 fluid-bed. A polymer solution of ethylcellulose and dibutylsebacate in ethanol was prepared, which was then coated onto caffeinecores in Glatt GPCG-3 with a 4″ Wurster insert. The release of caffeinewas assayed as described above.

As shown in Table 5, 50% of the starting dose of caffeine was releasedafter 10 hours whereas about 70% of the starting dose of caffeine wasreleased after 17 hours had elapsed. This indicates that thesequestering unit is unable to substantially prevent the release of thecaffeine over 24 hours.

An eighth sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Diltiazem HCl 5.0 Sugar Spheres (#16-18 mesh) 43.8Hydroxypropyl Cellulose 1.3 Ethylcellulose 10.0 Magnesium Stearate 1.0Total 60.1

Diltiazem was dispersed in an ethanolic solution of hydroxypropylcellulose using a mechanical stirrer. The resulting dispersion waslayered onto sugar spheres using a rotor granulation process in GlattGPCG-3 fluid-bed. A polymer solution of ethylcellulose in ethanol wasprepared and magnesium stearate was dispersed just prior to spraying.The polymer dispersion was then coated onto diltiazem cores in GlattGPCG-3 with a 4″ Wurster insert.

The release of diltiazem was assayed as described above for caffeineexcept that a wavelength of 236 nm was used to assay diltiazem.

As shown in Table 5, 25% of the starting dose of diltiazem was releasedafter about 13 hours had elapsed, whereas about 36% of the starting doseof diltiazem was released after 17 hours had elapsed. This indicatesthat the sequestering unit is unable to substantially prevent therelease of the caffeine over 24 hours.

A ninth sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Diltiazem HCl 5.0 Sugar Spheres (#20-25 mesh) 43.8Hydroxypropyl Cellulose 1.3 Eudragit RS PO 7.4 Sodium Lauryl Sulfate 0.3Dibutyl Sebacate 0.7 Magnesium Stearate 2.5 Total 60.1

Diltiazem was dispersed in a ethanolic solution of hydroxypropylcellulose with a mechanical stirrer. The resulting dispersion waslayered onto sugar spheres using a rotor granulation process in GlattGPCG-3 fluid-bed. A polymer solution of Eudragit RS, sodium laurylsulfate and dibutyl sebacate in ethanol was prepared, and magnesiumstearate was dispersed into the polymer solution just prior to spraying.The polymer dispersion was then coated onto diltiazem in Glatt GPCG-3with a 4″ Wurster insert. The release of diltiazem was assayed asdescribed above.

As shown in Table 5, more than about 1% of the starting dose ofdiltiazem was released after about 17 hours had elapsed. This suggeststhat this sequestering agent is capable of substantially preventing therelease of the aversive agent over a period of 17 hours, however, over20% was released at 24 hours. This suggests that this sequestering agentis unable to substantially prevent the release of diltiazem over aperiod of 24 hours.

A tenth sequestered form of an aversive agent comprised the followingcomponents:

Amount per unit (mg) Propranolol HCl 5.0 Sugar Spheres (#20-25 mesh)43.8 Hydroxypropyl Cellulose 1.3 Eudragit RS PO 7.4 Sodium LaurylSulfate 0.3 Dibutyl Sebacate 0.7 Magnesium Stearate 2.5 Total 60.1

Propranolol was dispersed in a ethanolic solution of hydroxypropylcellulose with a mechanical stirrer. The resulting dispersion waslayered onto sugar spheres using a rotor granulation process in GlattGPCG-3 fluid-bed. A polymer solution of Eudragit RS, sodium laurylsulfate and dibutyl sebacate in ethanol was prepared, and magnesiumstearate was dispersed into the polymer solution just prior to spraying.The polymer dispersion was then coated onto propranolol cores in GPCG-3with a 4″ Wurster insert. The release of propranolol was assayed asdescribed above for caffeine except that a wavelength of 290 nm was usedto assay propranolol.

As shown in Table 5, 50% of the starting dose of propranolol wasreleased after about 17 hours had elapsed, while 80% of the startingdose of propranolol was released after 24 hours had elapsed. This is thesame sequestering agent as used in the previous example and this showsthat although the two aversive agents used in the previous example andin this example are similar in molecular size and charge, they behavedifferently with this sequestering agent.

TABLE 5 % release at indicated timepoint (hours) 3 6 10 13 17 24 1^(st)intact dosage form 4 13.4 49.3 69.1 82.1 N/D 2^(nd) intact dosage form 715.7 31.2 46.1 64.5 N/D 3^(rd) intact dosage form 8.1 28.9 49.8 60.069.2 N/D 4^(th) intact dosage form 0 0.2 11.7 25.4 36.5 N/D 5^(th)intact dosage form 0.1 0.1 0.2 0.3 0.8 >20 6^(th) intact dosage form 1.30.4 0.8 7.8 55.8 N/D N/D = not determined

This example demonstrates the drawbacks of the sequestered forms of anagent disclosed by the prior art. The fifth dosage form, as shown inTable 5, released greater than 20% within 24 hours.

Example 2

This example demonstrates a sequestering subunit of the invention and amethod of making the same.

The sequestering subunit comprised the following components:

% Weight (g) Naltrexone Core 81.5 700.0 Eudragit RS PO 12.2 105.0 SodiumLauryl Sulphate 0.4 3.5 Magnesium Stearate 4.6 39.9 Dibutyl Sebacate 1.210.5 Ethyl Alcohol 541.1

This example was manufactured as described in the first form of Example1 except that the coating had the composition shown in the table above.The coating was applied to a 16% weight gain.

the release of naltrexone was determined as described in the first formof Example 1.

As shown in the table below, the release of naltrexone over 24 hours wasonly 3.4%, while the release over 48 hours was only 8.1%.

Timepoint (hours) % naltrexone released 0 0 6 0 12 0.4 16 1.7 20 2.6 243.4 48 8.1

Example 3

This example demonstrates that the mechanical fragility of asequestering subunit increases when the sequestering subunit is sealedwith a hydrophobic polymer, such as Surelease or Eudragit RS30D.

Crushing or fracture strength of sequestered adverse agent containingsubunits was measure using the TA.XTPlus Texture Analyser manufacturedby Texture Technologies Corporation of Scarsdale, N.Y. This instrumentconsisted of a movable arm containing a load cell that measured theresistance to movement of the arm. The arm can be raised or lowered overa fixed base and can be equipped with many different kinds of probes.The arm was driven up or down by a stepping motor. The rate of movementof the arm was controlled, and the force measured by the load cell wasrecorded, by a computer program. To measure the crushing strength ofparticles of about 1 mm in diameter, the unit was equipped with a 4 mmflat bottom probe. It was programmed to move the arm down at 0.1 mm persecond. A measured force of 10 g was used to determine the point ofcontact with the particle and so measure the height (diameter) of theparticle. Once contact was made, the probe continued to move downwardwith the measured force increasing more of less linearly until theparticle fractured, at which point the force measured abruptlydecreased. Further movement can detect secondary or tertiary cracking ofthe particle. The fracture force was the force being applied at themoment of abrupt decrease or cracking. The brittleness was a measure ofhow far the probe moves to re-contact the particle following cracking.

As shown in Table 6, sugar spheres of about 1 mm in diameter had afracture (or cracking) force of about 670 g (average of 10determinations). When sugar spheres were layered with naltrexone, thefracture force decreased by about 100 g. This was likely due to the thinlayer of naltrexone not being firmly bonded to the sugar sphere surfaceand hence cracking away from the sugar sphere surface. This phenomenonis sometimes referred to as “egg shelling” in the art. Sugar spherescoated with either ethylcellulose (Surelease) of acrylic based polymer(Eudragit RS30D) yielded a much stronger fracture force than do uncoatedsugar spheres. A force of the magnitude required to fracture thesecoating was greater than that required to fracture the naltrexone layer.

TABLE 6 Fracture Brittleness Product Force (g) (mm) Height (mm) Sugarspheres 673 0.097 0.913 Sugar spheres layered 575 0.073 0.903 withnaltrexone Sugar spheres sealed 1060 0.181 0.938 with Surelease Sugarspheres sealed 1065 0.139 0.948 with Eudragit RS30D

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1-38. (canceled)
 39. A method of treating pain in a human beingcomprising administering to the human being a plurality of compositesubunits, each composite subunit comprising a sequestering subunitcomprising naltrexone and a blocking agent comprising a surfactantwherein the blocking agent substantially prevents release of thenaltrexone from the sequestering subunit in the gastrointestinal tract,the sequestering subunit being overcoated with an opioid agonist inreleasable form.
 40. The method of 39 wherein the opioid agonist isselected from the group consisting of morphine, hydromorphone,oxycodone, and hydrocodone.
 41. The method of claim 40 wherein theopioid agonist is morphine.
 42. The method of claim 39 wherein theblocking agent further comprises a pharmaceutically acceptablehydrophobic material.
 43. The method of claim 42 wherein thepharmaceutically acceptable hydrophobic material is insoluble in thegastrointestinal tract.
 44. The method of claim 39 wherein thepharmaceutically acceptable hydrophobic material is a copolymer ofacrylic acid and methacrylic acid.
 45. The method of claim 44 whereinthe pharmaceutically acceptable hydrophobic material is Eudragit RSPO.46. The method of claim 45 wherein the surfactant is sodium laurylsulfate.
 47. The method of claim 39 wherein the plurality of compositesubunits are contained within a capsule.
 48. The method of claim 39wherein the plurality of composite subunits are contained within acapsule, the blocking agent comprises Eudragit RSPO, and the surfactantis sodium lauryl sulphate, and the opioid agonist is morphine.